1. Field of the Invention
This invention relates to the attenuation of nervous system damage after injury produced externally or by processes occurring within the organism itself. More particularly, the invention relates to the prevention of sequelae of nervous system injury by the coadministration of steroid hormones or steroid precursors such as pregnenolone, pregnenolone sulfate, and structurally similar organic compounds together with substances such as bacterial lipopolysaccharides (hereinafter referred to by the abbreviation LPS), ImuVert, muramyl dipeptide, and pyran or dextran polymers that stimulate secretion of cytokines by glia, monocytes, macrophages, and Schwann cells and with non-steroidal antiinflammatory substances or drugs (hereinafter referred to by the abbreviation NSAIDs) such as aspirin, indomethacin, ibuprofen, acetaminophen, sodium salicylate, BW755c, diclofenac, naproxen, and BF389 that suppress the inflammatory effects of enhanced activation of the above-mentioned non-neural cells while not diminishing the recovery-promoting effects of the cytokines secreted by them.
2. Description of the Prior Art
Externally initiated injuries to the nervous system are exemplified by contusions or compressions produced by direct blows to the head or spinal cord or by injuries to brain or spinal cord as a result of falls or other accidents; by penetrating wounds caused by knife blades, bullets, or other types of foreign objects or by complete severance of the spinal cord caused by such wounds; by X-rays, electromagnetic radiation, or exposure to radioactive fallout; by infections caused by bacteria, protozoa, yeast, fungi, or viruses. Indigenous modes of injury are exemplified by partial or complete occlusions of blood vessels by immune complexes, platelet aggregations, arteriosclerotic plaques, or sickle cell erythrocytes; by aneurysms, strokes, vascular spasms; by deposition of lipofuscin and/or amyloid; by autoimmune processes in allergic reactions, lupus erythematosus, and demyelinating disorders; by variously produced irritative inflammatory processes in endothelial cells of capillaries of blood vessels which result in permeabilization of blood vessels and the consequent edematous swelling in regions of the brain and spinal cord; or by invasive lesions caused by benign or malignant tumors.
Both regionally and globally, the whole functional terrain in the nervous system is disturbed after injury occurs. There is damage to microvasculature and there are losses of neuronal cells, decreases in neuronal processes in surviving cells, and increases in various glial elements and/or changes in their proportions and functions. Accelerated degeneration of neural, endothelial, neuroendocrine, and endocrine elements together with incoordination of the networks of relations among the cellular components of the immune system with coincident disruption of neurovascular relations and breakdown of the blood-brain barrier in the affected regions predispose to development of circulating and cellular autoantibodies to various polymeric cellular components of cellular and extracellular components in the disrupted regions. This leads to enhanced cellular destruction and deposition of the relatively indigestible debris of immune complexes in capillaries and extracellular sites. A further consequence of perturbation of the immune system is immunosuppression, with resultant activation of latent viruses destructive to the nervous system.
In view of the great complexity of the biological situations touched upon above and the ripple-like, radiating effects of injury, it is not surprising that there are changes in a myriad of measured parameters. A primary therapeutic task has been to identify key therapeutically-accessible, rate-limiting processes and to facilitate their relief. The remarkable self-organizing properties of biological systems often enable them to begin to function adaptively once effective communications among their relevant subunits are reinstituted.
Injuries to the nervous system have been treated in the past using supportive and surgical procedures. For example, many injuries have been treated simply by immobilizing the head and neck for a period of time. The recent advances in nursing and acute medical and rehabilitational care are largely responsible for the improved longevity of patients with spinal-cord injuries, but there have not been accompanying improvements in neurologic outcome. Only recently have advances been made that show medication can enhance recovery from nervous system damage. Specifically, Bracken et al. in The New England Journal of Medicine, 322:1405-1412 (May 17, 1990), reported that in patients with acute spinal-cord injury, treatment with methylprednisolone can improve neurologic recovery when the medication is given within the first eight hours after injury, however, treatment with naloxone does not improve neurologic recovery. The Bracken et al. study shows that methylprednisolone had no effect at low doses and was only effective at high, receptor saturating levels.